1. Field of the Invention (Technical Field)
The present invention relates to methods of making covalently cross-linked coatings for medical devices, and particularly cross-linked complex carbohydrate molecules such as heparin and related molecules, coatings made by such methods and medical devices including such coatings, particularly coated vascular graft devices.
2. Description of Related Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Vascular Prosthetic Devices. Vascular prostheses made of knitted or woven fabric of a polyester (e.g. DACRON® polyester, a trademark of E.I. du Pont de Nemours & Co., Inc.) or of sheets of polytetrafluoroethylene (commonly known under the TEFLON® trademark) are currently available or have been described in the art. Expanded polytetrafluoroethylene (ePTFE) tubes have a microporous structure consisting of small nodes interconnected with many tiny fibrilla. ePTFE is extruded into tubes to make vascular grafts. Although vascular grafts constructed using such material are generally clinically successful, there is a tendency for small bore vascular grafts to undergo thrombosis.
Several approaches have introduced polymers or coatings intended to minimize leaking around suture holes of the vascular prosthesis. U.S. Pat. No. 4,193,138 to Okita discloses introducing a water-soluble polymer into the pores of ePTFE material and then treating the polymer to render it water-insoluble. U.S. Pat. No. 5,665,114 to Weadock et al. disclosed filling the pores with solid biocompatible material of natural origin. A water-soluble substance is then introduced into the pores and treated to render it water-insoluble. For grafts made with knitted or woven fabrics, materials such as collagen or gelatin have been applied to the highly porous surface of such textiles. See, for example, U.S. Pat. Nos. 3,272,204; 4,747,848; 4,842,575 and 5,197,977. The materials are generally claimed to penetrate into the voids produced by the woven or knitted structure of the fabric and thus reduce blood leakage throughout the entire fabric, as well as at locations where sutures pass through the fabric. U.S. Pat. No. 6,368,347 to Maini et al. describes a layer of resilient, bioresorbable material on at least one wall where the material is substantially excluded from pores in the wall of the vascular prosthesis.
Heparin Coatings. A number of strategies have been described for complexing heparin to a surface for the purpose of rendering the surface thromboresistant. These methods include covalent conjugation of heparin directly to a substrate or alternatively adsorption of heparin onto a substrate. One example of an adsorbed heparin is U.S. Pat. No. 5,955,588 to Tsang et al., which describes a non-thrombogenic coating composition including a covalent complex of from 1 to 30 hydrophobic silyl moieties conjugated to heparin, with the hydrophobic silyl moieties bound to a surface via hydrophobic bonding interactions. A particular disadvantage of adsorbable heparins is that they generally have a short resident time in vivo and are easily leached over a period of hours. A number of direct conjugation procedures have been described in which heparin is either conjugated directly to the surface or conjugated via a spacer. Such chemistries are technically challenging and expensive, with some medical devices are not amenable to the chemistry. Medical devices made of polytetrafluoroethylene are particularly difficult to adapt to direct heparin conjugation strategies. Adsorption strategies suffer from the fact that the adsorbed materials are not covalently conjugated and are frequently quickly desorbed from the surface.
U.S. Pat. No. 6,096,798 to Luthra et al. describes polymers having non-thrombogenic properties that are prepared by copolymerizing monomers of at least three classes selected from (a) monomers having sulphate groups, (b) monomers having sulphonate groups, (c) monomers having sulphamate groups, (d) monomers having polyoxyalkylene ether groups, and (e) monomers having zwitterionic groups. The polymers can additionally be provided with anti-thrombogenic properties by including an additional co-monomer having a pendant heparin (or hirudin, warfarin or hyaluronic acid) group. In this method the polymer is prepared in a complex multistep chemistry, and then after preparation applied to a surface where it chemically reacts and results in polymer adhesion to the surface.
U.S. Pat. No. 6,258,371 to Koulik et al. describes a complex method of coating a biocompatible medical article that involves synthesizing, in an organic solvent and apart from the medical device, a mixture including a first hydrophobic monomer such as hydrophobic methacrylate or hydrophobic acrylate monomers, a second functional monomer having pendant chemically reactive amine groups capable of forming covalent bonds with biologically active compounds, and a third hydrophillic monomer, the synthesis yielding a co-polymer solution. The polymeric surface of the medical device is coated with the co-polymer solution and a biomolecule is then coupled onto the coated surface through the ordered steps of: (a) admixing heparin with a periodate solution, (b) reacting the admixture and adding cyanoborohydride, (c) diluting the reacted admixture and (d) treating the coated co-polymeric surface with the diluted reacted admixture to render the resulting treated and coated polymeric surface amphiphobic. A similar coating strategy is described in Koulik et al., U.S. Pat. No. 6,270,788.
Other patents disclosing various heparin coatings include U.S. Pat. Nos. 5,945,457, 6,309,660, 6,406,687, 6,458,889, 6,491,965, and 6,534,591, among others.
Use of Polyethylene Glycols in Coatings. Methods have been described using polyethylene glycols as coatings, both where the polyethylene glycols are applied passively, as described in U.S. Pat. No. 5,509,899, and where the polyethylene glycols are “preactivated” and conjugated directly to the surface. In order to be used as conjugated coatings, the polyethylene glycols need to “activated” such that they can be employed for covalent bonding. The activations typically involve modification of one or both of the terminal groups, for example so that hydroxyl groups of polyethylene glycol (PEG) are “activated”. This has been done by the use of a number of reactive functional groups including cyanurylate, tresylate, N-hydroxysuccinimide derived active esters, carbonates, imidazolyl formates, 4-dithiopyridines, isocyanates, and epoxides.
Methods to attach activated PEGs directly to the surface of medical devices are described in U.S. Pat. No. 5,650,234 to Dolence et al. and U.S. Pat. No. 6,099,562 to Ding and Helmus. U.S. Pat. No. 5,650,234 to Dolence et al. describes mixed carbonate analogs of PEG that smoothly react with amino groups in aminoglycans and protein- and amino-containing surfaces to form stable, hydrolysis-resistant carbamate linkages. In one embodiment applied to a stainless steel substrate, surfaces are treated with a glow-discharge plasma to etch the surface, re-treated with a glow-discharge plasma to introduce a polymeric siloxane, treated yet again with a glow-discharge plasma to introduce amines, conjugated with activated PEG in large molar excess to conjugate one (but not both) ends of the PEG, and then conjugate to aminoglycans via the remaining activated site on the PEG. This coating is durable, but the method is cumbersome and requires a large number of steps. U.S. Pat. No. 6,099,562 describes a layered coating for release of biologically active materials including heparin, where the coating includes a polymeric undercoat incorporating a biologically active material, with a topcoat formed of a discontinuous coating disposed over the entire outer surface of the undercoat, thereby forming covered and uncovered areas of the undercoat throughout the entire outer surface. The topcoat can then be modified with an ammonia plasma to introduce amines and conjugate PEG. In this method the use of multiple layers is cumbersome. Both U.S. Pat. No. 5,650,234 and U.S. Pat. No. 6,099,562 used glow-discharge methods which are limited to coating “line-of-sight” surfaces, and are not generally applicable to devices with complex geometries, such as tubes or matrices.
U.S. Pat. No. 5,510,418 describes a biocompatible, biologically inert conjugate including a chemically derivatized glycosaminoglycan conjugated to a synthetic hydrophilic polymer, which may include a polyethylene glycol. This method teaches the use of such complexes as three-dimensional matrices. Coatings of this invention are accomplished by dipping the device into a solution containing glycosaminoglycan and synthetic polymer while crosslinking is occurring and allowing the adherent viscous coating to dry as crosslinking is completed. The use of a viscous coating results in a thick coating and makes penetration of matrices difficult. Furthermore, coatings of tubes are prone to variations in thickness along the length of the tubes due to wicking during drying. The method does not teach a way of allowing the heparin to interact with the surface to prolong resident time either by covalent conjugation to the surface or by adsorption methods.
It can be seen that the foregoing methods do not provide a simple and durable heparin coating, preferably a cross-linked heparin coating, which can be applied by means of simple chemistry steps, and particularly applied to microporous structures such as vascular grafts made from ePTFE. Thus a simple method of making a cross-linked heparin or other biomolecule coating on a surface to provide a durable thromboresistant coating is needed.